ITI-007 Hydrochloride Polymorphs for Stable, Soluble Formulations
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Solution Overview
Problem
Existing formulations of ITI-007, a potent 5-HT2A receptor ligand, face challenges due to its oily, sticky solid form and poor aqueous solubility, with previously identified hydrochloride salt forms being hygroscopic and unstable.
Innovation Solution
Development of three new stable hydrochloride polymorphs of ITI-007 through extensive screening, which are crystalline and suitable for pharmaceutical formulations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If the free base form of ITI-007 is used, then good solubility in organic solvents is achieved, but poor aqueous solubility and oily sticky solid form occur
Solution Approach 1:
The patent changes the chemical form of ITI-007 from free base to hydrochloride salt, fundamentally altering its solubility parameters. This transformation enables the compound to achieve good aqueous solubility while maintaining a stable crystalline solid form, directly resolving the contradiction between aqueous solubility and physical form.
Solution Approach 2:
The patent creates a composite salt structure by combining ITI-007 with hydrochloric acid to form a hydrochloride salt. This composite material exhibits improved aqueous solubility and stable crystalline properties, overcoming the limitations of the free base form.
2Quantity of substance
If previously identified hydrochloride salt forms are used, then aqueous solubility is improved, but hygroscopicity and instability occur
Solution Approach 1:
The patent systematically varies crystallization parameters including solvent type, temperature, and pH to obtain a stable crystalline hydrochloride salt form. This controlled parameter change eliminates hygroscopicity and instability while preserving aqueous solubility, directly addressing the contradiction between solubility and stability.
Solution Approach 2:
The patent utilizes controlled phase transitions during crystallization to form a stable solid state structure. By carefully controlling the crystallization process, the patent achieves a non-hygroscopic crystalline form that is stable while maintaining good aqueous solubility.
3Reliability
If extensive salt screening is performed, then new stable salt forms are discovered, but time and resource consumption increase
Solution Approach 1:
The patent performs preliminary solubility testing and preliminary salt formation experiments to identify promising candidates before conducting extensive screening. This preliminary action filters out unsuitable salts early, reducing the time and resources needed for comprehensive screening while ensuring reliable stable salt forms are discovered.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The new hydrochloride salt forms provide improved stability and solubility, facilitating the preparation of galenic formulations for treating conditions involving 5-HT2A receptor signaling pathways.
Implementation Method 1
three new hydrochloride polymorphs were discovered. These hydrochloride salt forms are crystalline and stable
Data Source
AI summary
The disclosure provides new, stable, pharmaceutically acceptable hydrochloride salt forms of 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H -pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one, together with methods of making and using them, and pharmaceutical compositions comprising them.